Neonatal Bartter Syndrome Research Articles

Coexistence of Neonatal Bartter Syndrome and Congenital Cutis Laxa, in which a new mutation in SLC12A1 was identified

Introduction: Neonatal Bartter Syndrome (NBS) is an extremely rare congenital chronic renal tubular transport disorder characterized by preterm birth, polyhydramnios, polyuria, salt wasting, and severe dehydration. Congenital Cutis Laxa (CCL) is a rare disease characterized by loss of skin flexibility and laxity, and atypical facial appearance.
 Case Presentation: A 1290-gram female baby at 30+6 weeks of gestation was hospitalized due to premature birth and respiratory distress. During physical examination, an atypical facial appearance, wrinkles on the forehead, skin laxity, and philtrum were visible as well as a small chin and arachnodactyly in the fingers and toes. The patient displayed metabolic alkalosis in her blood gases. The patient, with an atypical face and current findings submitted her exome for genetic diagnosis. Genetic analysis revealed the presence of homozygous NM_001184832.2:c.2485+5G>A (rs749269268) in SLC12A1, and NBS Type 1 was diagnosed. A novel heterozygous NM_000501.4:c.352G>T, p.Val118Phe (rs781922544) variant was detected in ELN, and CCL syndrome with autosomal dominant inheritance was diagnosed.
 Conclusions: The rare co-occurrence of NBS and CCL syndrome in our patient was seen as a mere coincidence. Since this is the first reported case in the literature, it was deemed appropriate to present this case.

Neonatal Bartter syndrome diagnosed by rapid genomics following low risk pre-conception carrier screening.

Advances in the speed and accessibility of genomic sequencing are broadening the application of this technology to rapid, acute care diagnostics and pre‐conception carrier screening. In both circumstances, genetic counselling plays a critical role in preparing couples for the strengths and limitations of the testing. For pre‐conception carrier screening in particular, it is important that parents and clinicians are aware that even in the absence of an identified risk for recessive disease, a baby with a genetic condition may still be conceived. As an example, we present the genomic journey of a couple who underwent pre‐conception carrier screening and following a low‐risk result, delivered a baby boy who was diagnosed with Type 1 Bartter syndrome. Ultra‐rapid, post‐natal, trio whole genome sequencing resolved both parents as carriers of pathogenic variants in SLC12A1, a gene not included in the original pre‐conception screening panel. This family's story highlights (i) the intricacy of gene selection for pre‐conception screening panels, (ii) the benefits of high‐quality pre‐test genetic counselling in supporting families through adverse genomic findings and (iii) the role rapid genomics can play in resolving uncertainty for families and clinicians in circumstances where suspicion of genetic disease exists. This article is accompanied by a Patient Voice perspective written by the child's parents, placing emphasis on the essential role genetic counselling played in their journey.

Neonatal Bartter syndrome: A case report from Northern India

Abstract. Bartter Syndrome is a rare genetic disorder affecting the renal tubular system causing a decreased absorption of sodium and chloride in the thick ascending limb of the Henle loop. Most children present in infancy with complaints of polyuria, polydipsia, vomiting, constipation and failure to thrive while older children present with recurrent episodes of dehydration, muscle weakness and cramps. The present study aimed to demonstrate a case of Bartter syndrome presenting as acute gastroenteritis.

Neonatal Bartter syndrome with solute carrier family 12 member 1 gene mutation: a case report

本文报道了1例溶质载体家族12成员1（solute carrier-family 12 member 1，SLC12A1）基因突变致新生儿巴特综合征的诊疗过程。患儿胎龄30周+4，生后表现为生长发育迟缓，频繁呕吐、发热、脱水、多尿等；实验室检查显示难以纠正的低钾血症、低氯血症、代谢性碱中毒及高醛固酮血症；同时，基因检测显示患儿SLC12A1基因为复合杂合突变，确诊为巴特综合征。提示当新生儿临床上出现生长迟缓、多尿，以及难以纠正的低血钾、低氯碱中毒时，应警惕新生儿巴特综合征，尽早行基因检测确诊。

Neonatal Bartter Syndrome

The neonatal form of Bartter syndrome is characterized by intrauterine onset of polyuria leading to severe polyhydramnios. We report a case of a 31 weeks, male baby was born by emergency Caesarean Section due to severe polyhydramnios (AFI 54). Postnatally, baby had polyuria, dehydration, hyponatremia, hypokalemia and hypochloremic metabolic alkalosis. Possibility of neonatal Bartter syndrome was supported by high serum renin and aldosterone levels. Correction of electrolytes and dehydration along with indomethacin constituted the treatment. This syndrome is reported to make paediatricians aware about the severe neonatal form of the disease.J Nepal Paediatr Soc 2016;36(2):204-207.

A Case Report on Neonatal Bartter Syndrome and It’s Effective Management-Clinical Pharmacist Perspective

Bartter Syndrome is an inherited renal tubular disorder with hypokalaemia, hypochloremic and metabolic alkalosis. The syndrome was diagnosed by elevated serum renin levels, which is seen in our case, improved with potassium supplements and Indomethacin. In some patients Indomethacin therapy failed to resolve or prevent nephrocalcinosis. We are reporting a case of neonatal bartter syndrome responded well to Indomethacin and appropriate electrolyte therapy which gradually improved the general condition of the child. Unless there is a high degree of suspicion, patients may go undiagnosed or may be incorrectly managed for protein–energy malnutrition. Early diagnosis helps in improving the outcome by Angiotensin converting enzyme inhibitors (ACE) and NSAID’s.

Neonates with Bartter syndrome have enormous fluid and sodium requirements.

Managing neonatal Bartter syndrome by achieving adequate weight gain is challenging. We assessed the correlation between weight gain in neonatal Bartter syndrome and the introduction of fluid and sodium supplementations and indomethacin during the first 4 weeks of life. Daily fluid and electrolytes requirements were analysed using linear regression and Spearman correlation coefficients. The weight gain coefficient was calculated as daily weight gain after physiological neonatal weight loss. We studied seven infants. The highest weight gain coefficients occurred between weeks two and four in the five neonates who either received prompt amounts of fluid (maximum 810 mL/kg/day) and sodium (maximum 70 mmol/kg/day) or were treated with indomethacin. For the two patients with the highest weight gain coefficient, water and sodium supplementations were decreased in weeks two to four leading to a significant negative Spearman correlation between weight gain and fluid supplements (r = -0.55 and -0.68) and weight gain and sodium supplementations (r = -0.96 and -0.72). The two patients with the lowest weight gain coefficient had positive Spearman correlation coefficients between weight gain and fluid and sodium supplementations. Infants with neonatal Bartter syndrome required rapid and enormous fluid and sodium supplementations or the early introduction of indomethacin treatment to achieve adequate weight gain during the early postnatal period.

Bartter syndrome: presentation in an extremely premature neonate

Reports of Bartter syndrome in premature neonates are rare. We describe the presentation and clinical course of a neonate born at 25.6 weeks estimated gestational age with polyuria, hyponatremia, hypokalemia and hypercalciuria ,who was diagnosed with neonatal Bartter syndrome. The evaluation, diagnosis and management of neonatal Bartter syndrome in this premature neonate are discussed.

QT and JT dispersion and cardiac performance in children with neonatal Bartter syndrome: a pilot study

QT dispersion and JT dispersion are simple noninvasive arrhythmogenic markers that can be used to assess the homogeneity of cardiac repolarization. The aim of this study was to assess QT and JT dispersion and their relation with left ventricular systolic and diastolic functions in children with Bartter syndrome (BS). Nine neonatal patients with BS (median age 9.7 years) and 20 controls (median age 8 years) were investigated at rest. Both study and control subjects underwent electrocardiography (ECG) in which the interval between two R waves and QT intervals, corrected QT, QT dispersion, corrected QT dispersion, JT, corrected JT, JT dispersion and corrected JT dispersion were measured with 12-lead ECG. Two-dimensional, Doppler echocardiographic examinations were performed. Patients and controls did not differ for gender and for serum levels of potassium, magnesium, and calcium (p > 0.05). Both study and control subjects had normal echocardiographic examination and baseline myocardial performance indexes. The QT dispersion and JT dispersion were significantly prolonged in patients with BS compared to those of the controls {37.5 ms [interquartile range (IQR) 32.5-40] vs. 25.5 ms (IQR 20-30), respectively, p = 0.014 and 37.5 ms (IQR 27.5-40) vs. 22.5 ms (IQR 20-30), respectively, p = 0.003}. Elevated QT and JT dispersion during asymptomatic and normokalemic periods may be risk factors for the development of cardiac complications and arrhythmias in children with BS. In these patients the need for systematic cardiac screening and management protocol is extremely important for effective prevention.

Neonatal Bartter syndrome and unilateral ectopic renal cyst as new renal causes of hydrops fetalis: two case reports and review of the literature

Non-immune hydrops fetalis (NIHF) is a challenging entity as it represents the end stage of several different disorders. Renal and genitourinary causes of NIHF are rare and include congenital renal malformations, tumors and ureter-urethra disorders. Herein, two NIHF cases with different renal causes were presented. The first case that had antenatal NIHF was diagnosed neonatal Bartter syndrome. The second case of NIHF with antenatal large cyst in the surrenal gland area required surgery and ectopic renal cyst was diagnosed. To our best of knowledge, these are the first reports of NIHF associated with neonatal Bartter syndrome and ectopic renal cyst in neonates. Although it may be coincidental, these cases suggest that both neonatal Bartter syndrome and unilateral ectopic renal cyst may cause NIHF development in neonates by several different mechanisms. Therefore, these two rare entities should be suspected in cases of NIHF with similar findings.

Neonatal Bartter syndrome associated with ileal atresia and cystic fibrosis

A rare case of neonatal Bartter syndrome presenting with severe hyperkalemia is reported in a preterm child born to consanguineous parents. This child also had ileal atresia, and meconium plugs were found at laparotomy. The diagnosis of cystic fibrosis was subsequently made on genetic testing. Despite full intensive care management and surgical interventions, he died of respiratory failure after 70 days. This is the first reported case of such conglomeration of pathologies in a newborn child. Second, in highlighting this case we want clinicians to be aware that a subtype of neonatal Bartter syndrome can present with initial hyperkalemia so that an erroneous diagnosis of pseudohypoaldosteronism is not made when this is seen in combination with hyperkalemia and hyperrenin hyperaldosteronism.

Nephrocalcinosis and Placental Findings in Neonatal Bartter Syndrome

Neonatal Bartter syndrome (NBS) is an inherited renal tubular disorder associated with hypokalemic alkalosis. Here we report a case of genetically diagnosed NBS. Polyhydramnios was noted at 26 weeks. A boy was born at 31 weeks and 1 day, weighed 1344 g, and had an Apgar score of 8/8. We initiated indomethacin (IND) at a dose of 0.2 mg/kg/d on day 31, and increased it to approximately 3 mg/kg/d. However, his urinary calcium (Ca) levels remained unchanged. At 4 months of age, nephrocalcinosis was detected by ultrasound. The placenta weighed 700 g (+2.7 standard deviations). Although the proportion of terminal villi was consistent with the gestational age, many of them exhibited poorly dilated capillaries. Hemosiderin pigment was seen throughout the amniochorionic connective tissue and along about 50% of the trophoblast basement membrane (TBM). Von Kossa stain revealed the corresponding area of mineralization along the TBM. In our opinion, urinary Ca levels were high and did not change after IND initiation, indicating that nephrocalcinosis may be inevitable. Enhanced inflow of maternal plasma through the basement membrane would cause Ca deposition, given that the same finding was obtained in the case with polyhydramnios. The same mechanism would also explain the hemosiderin pigment distribution.

Status epilepticus as the only presentation of the neonatal Bartter syndrome

Bartter syndrome is a rare hereditary (autosomal recessive) salt-losing tubulopathy characterized by hypokalemia, hypochloremia, metabolic alkalosis, and normal blood pressure with hyperreninemia, The underlying renal abnormality results in excessive urinary losses of sodium, chloride, and potassium. We report a case of a four-month-old infant with neonatal Bartter syndrome, who presented only with status epilepticus. To the best of our present knowledge, there is no reported case of Bartter syndrome who presented with status epilepticus.

Type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea

SummaryBackground:Pseudo-Bartter syndrome encompasses a heterogenous group of disorders similar to Bartter syndrome. Sometimes a few status may be nested, as in our case presented here.Case Report:An 8-month-old boy was referred to our hospital with of intractable diarrhea, polyuria, persistent hypokalemia, abdominal distension and failure to thrive. He was born in the 34 6/7 gestational week (GW) to consanguineous parents. In the 30th GW polyhydramnios was verified by ultrasonography. The laboratory results showed hypokalemic-hypochloremic metabolic alkalosis, hyponatremia, and increased urinary loss of chloride, potassium and calcium. An audiogram test revealed complete sensorineural deafness. Ultrasonography revealed medullary nephrocalcinosis in both kidneys. Elevated plasma renin activity and aldosterone were found and a provisional diagnosis of type-IV neonatal Bartter syndrome was made. Treatment with indomethacin, spironolactone and additional intake of NaCl/KCl was initiated. Despite these therapies, the child’s diarrhea persisted but serum potassium concentration normalized, and hypercalciuria and urine output reduced. After determining the high fecal chloride concentration, there was an immediate decompensation of the disease on indomethacin withdrawal, thus a diagnosis of type IV neonatal Bartter syndrome complicated with congenital chloride diarrhea was considered. Indomethacin, spironolactone and supplementary therapies with NaCl/KCl were continued, which resulted in the normalization of serum electrolytes as well as his physical development, but high contents of chloride in urine and faeces and nephrocalcinosis remains unchanged during 1-year follow-up.Conclusions:Because of the clinical and laboratory simulations between the various diseases that lead to hypokalemic-hypochloremic metabolic alkalosis, patients must be evaluated carefully.

Genetic basis of Bartter syndrome in Korea

Bartter syndrome (BS) is clinically classified into antenatal or neonatal BS (aBS) and classic BS (cBS) as well as five subtypes based on the underlying mutant gene; SLC12A1 (BS I), KCNJ1 (BS II), CLCNKB (BS III), BSND (BS IV) and CASR (BS V). Clinico-genetic features of a nationwide cohort of 26 Korean children with BS were investigated. The clinical diagnosis was aBS in 8 (30.8%), cBS in 15 (57.7%) and mixed Bartter-Gitelman phenotype in 3 cases (11.5%). Five of eight patients with aBS and all 18 patients with either cBS or mixed Bartter-Gitelman phenotype had CLCNKB mutations. Among the 23 patients (46 alleles) with CLCNKB mutations, p.W610X and large deletions were detected in 25 (54.3%) and 10 (21.7%) alleles, respectively. There was no genotype-phenotype correlation in patients with CLCNKB mutations. Twenty-three (88.5%) of the 26 BS patients involved in this study had CLCNKB mutations. The p.W610X mutation and large deletion were two common types of mutations in CLCNKB. The clinical manifestations of BS III were heterogeneous without a genotype-phenotype correlation, typically manifesting cBS phenotype but also aBS or mixed Bartter-Gitelman phenotypes. The molecular diagnostic steps for patients with BS in our population should be designed taking these peculiar genotype distributions into consideration, and a new more clinically relevant classification including BS and Gitelman syndrome is required.

Hypochloremic metabolic alkalosis and failure to thrive: question

The patient was born at 36 weeks of gestation with a birth weight of 2,850 g as the first living male child of consanguineous apparently healthy parents from Libya. The pregnancy had been complicated by polyhydramnios. The mother reported two previous pregnancies, one resulting in early abortion, and the other in an anencephalic neonate. After birth, the patient showed prolonged jaundice, vomiting, and dehydration with hypokalemia, and the clinical diagnosis of neonatal Bartter syndrome was made. Initial treatment included intravenous fluids to correct hypovolemia and oral potassium solutions. The further clinical course was characterized by persistent diarrhea (8–9/day stools daily) complicated by frequent episodes of dehydration and waterelectrolyte-imbalances leading to repeated hospitalizations. Because of the unremitting course and progressive failure to thrive, it was decided to refer the patient to our institution for further diagnosis and therapy. A review of previous hospital records showed that the patient had needed daily potassium supplements. Since the child strongly disliked the salty flavor of potassium chloride, an oral potassium gluconate solution had been given at a dose of 8 mmol/kg/day. Medication and feeding had remained difficult and the child had never developed normal eating patterns, resulting in a dependence on continuous oral feeding by relatives with occasional intravenous alimentation; however, application by a nasogastric tube had been refused by the parents. Celiac disease had been excluded by intestinal biopsy. Medication with omeprazole and domperidone was without effect. Altogether, the child had spent almost half of his life in hospitals. Upon admission, at the age of 2 years, the child appeared severely malnourished and weight (8,900 g), height (81.5 cm), and head circumference (45 cm) were far below appropriate percentiles for his age. Apart from abdominal distension and paleness, clinical examination revealed no further abnormalities and no congenital malformations. Blood gas analysis showed severe metabolic alkalosis (pH 7.58, bicarbonate 46 mmol/l, and base excess +21 mmol/l). Serum electrolytes were as follows: potassium 2.0 mmol/l, sodium 131 mmol/l, and chloride 68 mmol/l. Further clinical observation after rehydration and during a period of minimal intravenous fluid replacement showed that the patient had a spontaneous total caloric intake of approximately 20% of his recommended dietary allowance and a spontaneous fluid intake of about 200 ml.

Phenotype–genotype correlation in antenatal and neonatal variants of Bartter syndrome

Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype. Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years. We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life. We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.

Particularités diagnostiques du syndrome de Bartter néonatal chez le nouveau-né grand prématuré

Neonatal Bartter syndrome is a rare condition, usually revealed by alkalosis and hypokalemia. Clinical and biological signs of neonatal Bartter syndrome are quite different from those encountered when this disease is diagnosed in older children. Diagnosis of neonatal Bartter syndrome is even more difficult in very preterm infants. The aim of this study was to highlight specific clinical and biological signs that may help direct physicians towards the diagnosis of neonatal Bartter syndrome when premature infants present with an atypical renal tubular disorder. Our case reports focus on excessive diuresis with elevated renal sodium excretion and severe dehydration. Correcting tubular disorders early may help avoid dehydration in the fragile preterm newborn.

BARTTER SYNDROME PRESENTING AS POOR WEIGHT GAIN AND ABDOMINAL MASS IN AN INFANT

Bartter syndrome, a group of disorders that encompasses multiple genetic defects with similar clinical presentation, has been divided into six different genotypes, according to different genetic defects, and into three main clinical variants (or phenotypes). Classic laboratory findings in all variants include hypochloremia, hypokalemia, and metabolic alkalosis with excessive excretion of chloride and potassium. Classic Bartter syndrome, neonatal Bartter syndrome, and Gitelman syndrome are the three main clinical variants. Classic Bartter syndrome and neonatal Bartter syndrome have defects in genes that affect transport channels in the ascending loop of Henle, where as in Gitleman syndrome the defect occurs in the transport channels of the distal convoluted tubule. Classic Bartter syndrome and neonatal Bartter syndrome have similar presenting symptoms, potential outcomes, and treatment, but different ages at presentation. Gitelman syndrome, a more benign condition than the other clinical variants, has the classic hallmark finding of hypomagnesemia and low to normal excretion of calcium. This differentiates it from the classic and neonatal variants of the disease. With early diagnosis and proper treatment, Bartter syndrome has a good prognosis. But failure to identify it can lead to tubulointerstitial nephritis and renal failure. We present a case of a 6-month-old boy with Bartter syndrome who presented with poor weight gain and an abdominal mass.

Polyhydramnion, Frühgeburtlichkeit, Dystrophie, Polyurie, Obstipation, Nephrokalzinose und renale Raumforderung: Präsentation einer klassischen Tubulopathie

A diagnostic workup of a renal mass will rarely lead to the diagnosis of a tubulopathy. We would like to stress the importance of taking a detailed history and of evaluating these findings in the context of the clinical symptoms. A 3 year old boy with a renal mass, diagnosed due to urinary tract infection, was referred to exclude renal malignancy. Detailed history revealed polyuria and polydipsia in a child with preterm delivery due to polyhydramnios. These symptoms, together with poor thriving are highly suggestive of a neonatal form of Bartter syndrome. This diagnosis was substantiated by ultrasound findings of nephrocalcinosis and urolithiasis due to hypercalciuria and a renal abscess. Detection of mutations in the KCNJ1-gene confirmed the diagnosis. After unilateral nephrectomy for acute destructive nephritis and under medication with indomethacin and potassium citrate the patient is now thriving well. Renal masses suspicious of malignancy may distract from a hereditary tubulopathy. Typical clinical history and presentation with prematurity, polyhydramnios, polyuria, poor thriving and urolithiasis requires diagnostic evaluation of tubular function since routine laboratory tests and urinary dip stick may be normal. Unrecognized, neonatal Bartter syndrome may lead to severe complications including loss of kidney function.